chr1-42930865-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_006516.4(SLC2A1):c.277C>T(p.Arg93Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,600,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R93Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SLC2A1
NM_006516.4 missense, splice_region

Scores

Splicing: ADA: 0.9721

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 2.92

Variant links:

Genes affected

SLC2A1 (HGNC:11005): (solute carrier family 2 member 1) This gene encodes a major glucose transporter in the mammalian blood-brain barrier. The encoded protein is found primarily in the cell membrane and on the cell surface, where it can also function as a receptor for human T-cell leukemia virus (HTLV) I and II. Mutations in this gene have been found in a family with paroxysmal exertion-induced dyskinesia. [provided by RefSeq, Apr 2013]

SLC2A1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_006516.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-42930864-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 623684.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2, Pathogenic=1}.

PP2

Missense variant in the SLC2A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 98 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 2.9256 (below the threshold of 3.09). Trascript score misZ: 4.6729 (above the threshold of 3.09). GenCC associations: The gene is linked to childhood absence epilepsy, dystonia 9, epilepsy, idiopathic generalized, susceptibility to, 12, GLUT1 deficiency syndrome, myoclonic-astatic epilepsy, childhood onset GLUT1 deficiency syndrome 2, hereditary cryohydrocytosis with reduced stomatin, encephalopathy due to GLUT1 deficiency.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.944

PP5

Variant 1-42930865-G-A is Pathogenic according to our data. Variant chr1-42930865-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-42930865-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-42930865-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC2A1	NM_006516.4 link	c.277C>T	p.Arg93Trp	missense_variant, splice_region_variant	Exon 4 of 10	ENST00000426263.10	NP_006507.2	P11166Q59GX2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC2A1	ENST00000426263.10 link	c.277C>T	p.Arg93Trp	missense_variant, splice_region_variant	Exon 4 of 10	1	NM_006516.4	ENSP00000416293.2		P11166

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1448682

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721034

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Mar 14, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously in a mother and her two children with variable features ranging from mild to severe intellectual disability, ataxia, chorea, and/or seizures (PMID: 20129935); Published functional studies suggest that this variant is associated with reduced glucose uptake (PMID: 18387950); This variant is associated with the following publications: (PMID: 18403583, 29303961, 31302675, 23448551, 23106342, 24847886, 24824604, 26986070, 21445818, 33163569, 31440721, 36054588, 20129935, 18387950, 19996082) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Encephalopathy due to GLUT1 deficiency

Pathogenic:2

Apr 11, 2023

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 10, 2019

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant c.277C>T, p.Arg93Trp has been reported in multiple individuals with GLUT1 deficiency syndrome [MIM#606777] [PMID: 24847886; PMID: 2344855; PMID:23106342; PMID: 19996082]. This mutation is located in the first cytosolic loop of the protein [PMID: 19996082]. The variant has 0.003% allele frequency in the gnomAD database (1 out of 31,368 heterozygous alleles) indicating this is a rare variant and in silico tool predicts the variant is expected to be deleterious. Functional studies suggest that the variant results in reduced glucose uptake [PMID: 18387950]. Based on the available evidence, the variant c.277C>T, p.Arg93Trp in the SLC2A1 gene is classified as pathogenic. -

SLC2A1-related disorder

Pathogenic:1

Aug 18, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SLC2A1 c.277C>T variant is predicted to result in the amino acid substitution p.Arg93Trp. This variant has been reported in multiple individuals with GLUT1 deficiency (Joshi et al. 2008. PubMed ID: 18403583; Arsov et al. 2012. PubMed ID: 23106342; Ramm-Pettersen et al. 2013. PubMed ID: 23448551; Supplemental Table for Symonds et al. 2019. PubMed ID: 31302675) and an individual with alternating hemiplegia of childhood (Rotstein et al, 2009. PubMed ID: 19996082). An alternate substitution of the same amino acid has also been reported in association with GLUT1 deficiency (Magrinelli et al. 2020. PubMed ID: 32753446). In a functional study, the p.Arg93Trp substitution was reported to reduce glucose transport in erythrocytes (Pascual et al. 2008. PubMed ID: 18387950) This variant is reported in 0.029% of alleles in individuals of European (Finnish) descent in gnomAD (1 of 31,368 total alleles in http://gnomad.broadinstitute.org/variant/1-43396536-G-A). This variant is interpreted as pathogenic or likely pathogenic by multiple independent submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/16117). Based on the collective evidence, this variant is interpreted as pathogenic. -

Childhood onset GLUT1 deficiency syndrome 2

Pathogenic:1

Dec 08, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

GLUT1 deficiency syndrome 1, autosomal recessive

Pathogenic:1

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 93 of the SLC2A1 protein (p.Arg93Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with low cerebral spinal fluid blood glucose concentrations, findings that are highly specific for GLUT1 deficiency syndrome (PMID: 18403583, 19996082, 20129935, 23106342, 23448551). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16117). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

Seizure

Pathogenic:1

Aug 03, 2021

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

D;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Uncertain

0.64

MutationAssessor

Pathogenic

3.8

H;.

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.2

D;.

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0060

D;.

Sift4G

Uncertain

0.0050

D;D

Polyphen

1.0

D;.

Vest4

0.96

MutPred

0.75

Gain of catalytic residue at M96 (P = 0.0048);.;

MVP

0.95

MPC

2.1

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.86

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Benign

0.68

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over